Generation of an angiostatin-like fragment from plasminogen by stromelysin-1 (MMP-3)

Matrix metalloproteinase-3 (MMP-3 or stromelysin-1) specifically hydrolyzes the Glu(59)-Asn(60), Pro(447)-Val(448), and Pro(545)-Ser(545) peptide bonds in plasminogen, yielding a 55 kDa NH2-terminal angiostatin-like domain (comprising kringles 1-4), a 14 kDa domain comprising kringle 5, and a 30 kDa domain comprising the serine proteinase domain. The conversion is completely abolished in the presence of the MMP inhibitors EDTA or 1,10-phenanthroline. Biospecific interaction analysis indicates that binding of proMMP-3 and MMP-3 to plasminogen occurs with comparable affinity (K-A of 4.7 x 10(6) and 4.1 x 10(6) M-1, respectively) and is mediated via the miniplasminogen moiety (kringle 5 plus the proteinase domain) and via the catalytic domain of MMP-3. Thus, proteolytic cleavage of plasminogen by MMP-3 generates angiostatin-like fragments.